Decreased insulin sensitivity is a poorly understood phenomenon. We wish to determine if peripheral tissue resistance is characteristic of non-ketoacidotic diabetes mellitus. This will be investigated by comparing perfusions of single component insulin across the forearm of stable, non-obese diabetics and normal individuals made locally hyperglycemic. Hyperglucagonemia has been reported to be associated with catabolic states and diabetic ketoacidosis. However, the acute actions of this hormone upon forearm tissues have not been studied. Using perfusions of glucagon alone and simultaneous perfusions of both insulin and glucagon we will study the interaction of these two hormones upon human peripheral tissues. Systemic hyperinsulinemia (fasting and stimulated) is common to all insulin resistant states with normal carbohydrate tolerance. Chronic infusions of single component insulin (less than the amount required to reduce glucose concentrations) will be carried out in normal individuals to determine whether hyperinsulinemia, itself, will decrease the peripheral or systemic tissue sensitivity to exogenous insulin. The overall aim of these studies is (a) to investigate the existence of insulin resistance in diabetes mellitus and (b) to explore the genesis of insulin resistance in diabetes and in non-diabetic disorders with normoglycemia but resistance to exogenous insulin.